Methodology as the key for the future use of iPS cells in regenerative medicine

Clinical application of iPS cells

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Since the first derivation of embryonic stem cells (ESCs) from mouse and human embryos, much enthusiasm has been generated because the pluripotency of the cells (that is, their capacity to generate any cell type in the body) promised to revolutionize the field of regenerative medicine (in which diseased organs or tissues in a patient could be replaced or repaired by transplantation of cultured cells or an in vitro–generated tissue or organ). However, that promise has been often limited by the fact that, if used for transplantation, the origin of the cells from an allogeneic (genetically different but of the same species) donor blastocyst will most likely be recognized as “nonself” by the recipient immune system. In that regard, using ESC-derived cells or tissues for transplantation would be considered the same as using organs for transplantation from an allogeneic donor, with the need for lifetime immunosuppression and the associated complications. In addition, the fact that ESCs typically require the use and destruction of blastocyst-staged human embryos has elicited significant ethical considerations that have, in some cases, halted the progress of ESC research. All these obstacles have been solved by a single major discovery made by the team of Shinya Yamanaka in Japan. About a decade ago, Yamanaka started working on the possibility of converting adult somatic cells into pluripotent stem cells. To do so, he focused on a group of genes that were uniquely or highly expressed in ESCs. His team originally used retroviruses to overexpress 24 genes in mouse fibroblasts and amazingly found a few weeks later that colonies highly similar to normal mouse ESCs emerged in the culture plates. Unlike the starting fibroblast population, the resulting cells could be maintained indefinitely in culture and could function as ESCs. Moreover, they went further to demonstrate that only a cocktail of 4 out of the 24 genes, named Oct4, Klf4, Sox2, and cMyc (all of which encode proteins that function as transcription factors to regulate the expression of different sets of genes), were sufficient to induce nuclear reprogramming of somatic cells to bring them “back in time” to a primordial, pluripotent state. To distinguish these new cells from their embryonic counterparts, they were named induced pluripotent stem cells or iPS cells. It took a few months for the same team as well as other teams to show that the same principles could be applied to reprogram human somatic cells, a major step toward the long-sought use of pluripotent stem cells in regenerative medicine (Fig. 1). The functional demonstration that iPS cells were truly pluripotent was their ability to contribute to all types of tissues when injected into immunocompromised mice to form teratomas (tumors that contain tissues from all three primary germ layers). Most significantly, mouse iPS cells were capable of generating an entire mouse when injected into a mouse blastocyst.

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